PL86535B1 - Aminopyrazolopyrimidines and processes for their production[za7202689b] - Google Patents

Description

The subject of the invention is a process for the preparation of new 5-nitrofuran derivatives of the general formula I, in which R 4 is a lower alkyl radical, in particular methyl and ethyl acetate, and acid addition salts of these compounds. Acid addition salts, which can also be used as intermediates, e.g. for the purification of free compounds (consisting in converting the free compound into a salt, isolating the salt and then breaking down the salt), e.g. picrates, or for compound identification, are especially pharmacologically suitable, i.e. non-toxic, such as, for example, addition salts with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or with organic acids, such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or polyterocyclic acid -aliphatic carboxylic or sulphonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic acid, ablic, tartaric, lemon, ascrobic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, emtonic, methanesulfonic, 2-ethanesulfonic hydroxyethanesulfonic, ethylenesulfonic, halogenobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or N-cyclohexylsulfamic. Salts with the abovementioned acids are prepared in a known manner, for example by treating the free compounds with an acid or a suitable ion exchanger.

Claims (2)

For the sake of simplicity, the general formula 1 has been adopted as including all compounds, however, it should be taken into account that the compounds of formula 1 form tautomers, as illustrated in scheme I. A labile proton can be attached at the 2, 5 or 7 position of the ring system. The compounds of the general formula I as well as their addition salts have valuable antibacterial, antifungal, antimicroplasma, anthelmintic, antiprotozoal, and antimalarial properties as well as coccidiostatic, antifungal and antimalarial properties. These compounds can therefore be used in human and animal medicine as they are especially valuable in combating the most diverse microorganisms. These compounds are especially valuable in the treatment of urinary tract and gastrointestinal infections. Among the compounds of formula I, particularly valuable antimicrobial properties are exhibited by those compounds of formula I in which Rt is a lower alkyl radical, such as, in particular, methyl or ethyl. The antibacterial properties of the new compounds have been confirmed by a series of pharmacological studies which have shown that in vitro, for example, 4-amino-1-methyl-3- (5-nitro-2-fluyl) -1H-pyrazolo [ 3,4-d] -pyrimidines and 4-amino-1-methylp-3- (5-nitro-2-furyl) -1H-pyrazolo [3,4-d] - ^ 86 53,586 (35-pyrimidines work remarkably to inhibit the growth of cultures of Staphylococcus aureus, Escherichia salt, Klebsiella pneumoniae, Salmonella typhi and others. It has also been found that mice infected with a lethal dose of Staphylococcus aureous can be cured by oral administration of 4-amino-1-methyl-3-3. (5-nitro-furyl) -1H-pyrazolo [3,4-d] -pyrimidines. The new compounds are characterized by extremely low toxicity, e.g. in mice. The amount of therapeutic doses depends on the type of infection, species of animal, Its age and weight, and the average daily dose for mammals is 1- to 100 mg / kg of weight. It has been found that it is possible to prepare new 5-nitrofuran derivatives of general formula I, has the above meaning, when a compound of general formula II, in which Rt is as defined above, is preferably treated with formamide at reflux temperature and the compound of general formula I obtained is transformed into its addition salt with acid. The compounds of general formula II are known compounds described in South African Patent No. 70/1303 and can be prepared in a multistage reaction with nitrofurylnitrilimines of general formula III, in which Bt has the meaning given above. by reaction of these compounds with malonic acid dinitrile. The compounds according to the invention, optionally in the form of their acid addition salts, can be used for the preparation of pharmaceutical preparations containing at least one active ingredient of the formula I together with a pharmacologically acceptable solid carrier or liquid diluent. Suitable solid carriers are those generally known and usually used in the preparation of pharmaceutical preparations, with the selection of the carrier having advantages over the purpose for which the pmptrate is used. These preparations are therefore produced in a degreasing form and, for example, for external use - MfO, e.g. for disinfecting healthy skin or disinfecting * wounds, and possibly for the treatment of derinatosis and mucosal infections caused by bacteria, be produced as ma- M * fflMJnu ttnfctur. In order to obtain preparations in a form suitable for disinfecting the oral cavity, both preparations in the form of washing liquids and concentrates are used for their production, especially in the form of alcohol solutions containing 1-5% of the active substance and, if necessary, additionally containing glycerin and / or flavoring substances, as well as these preparations, can be used in the form of lozenges, i.e. tablets containing suitable, relatively low doses of active ingredient, e.g. 0.2-20% by weight, together with a relatively large amount of sugar or other like compound and other generally used adjuvants, as well as binding agent and flavorings. In order to obtain preparations suitable for oral use in the treatment, injection of the urinary tract, solid preparations, e.g. containing unit doses of tablets, dragees or capsules, e.g. containing 10-90%. 55 active ingredient. These preparations in this form are used in daily doses of 0.1-2.5 g for adults and correspondingly less for children. All the above-mentioned formulations can contain the active substance of the formula I itself or also other known pharmacologically active substances with antibacterial and / or antifungal activity, for example in order to extend the range of action of the compound according to the invention, such as, for example, 5.7. - dichloro-2-methyl-8-quinoline or other 8-quinoline derivatives, together with sulfamerazine or with sulfafurazole or other sulfanillamide derivatives, with chloroamphenicol or tetracycline and other antibiotics, such as 3,4 ', 5 acid anilide - tri-bromosalicylic or other halogenated salicylic acid anilide, together with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy diphenylmethane, with halohydroxy-diphenyl disulfides, with 4,4,-2-dichloride or 2-dichlorexide , 4,4, -trichloro-2-hydroxy-diphenylethers and other polyhalohydroxy diphenylpethers or with quaternary ballethericidal compounds, or with certain dithio acid derivatives carbamates, such as tetramethylthiouramide disulfide. It is also possible to use carriers which themselves already possess appropriate pharmacological properties, such as, for example, sulfur used as the basic powdery material or zinc stearate as a constituent of zinc ointments. Typical preparations may, for example, be prepared according to the recipes below. a) 250.0 g of the active ingredient is mixed with 550.0 g of lactose and 292.0 g of potato starch, the mixture is moistened with an alcoholic solution of 8 g of gelatine and then granulated through a suitable sieve. After drying, the granules are mixed with 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide, and the mixture is compressed to form tablets obtained from quantities of 10,000 units, each weighing 125 mg contains 25 mg of active ingredient. These tablets may optionally be provided with facilitating notches (bleaching them in parts. B) It is also possible to prepare a granulate with 100.0 parts of active ingredient * 37 M g of lactose and an alcoholic solution of 6 g of gelatine. After drying, this granulate is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talcum powder, 603 g of potato starch and 5.0 g of magnesium stearate and processed into 10,000 dragee cores. These cores are coated with a concentrated syrup made of 533.5 g of crystalline sucrose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talcum, 20.0 g of colloidal silicon dioxide and 1.5 g of a dye. and then dried. Each of the prepared pellets weighs 150 mg and contains 10 mg of active ingredient. The method according to the invention is illustrated by the example given below, in which temperatures are given in degrees Celsius. Example. A mixture of 5.0 g of 5-amino-4-cyano-1-methyl-3 (5-nitro-2-furyl) -pyrazole with 10 ml of formamide is kept at the end of intense reflux for 30 minutes. minutes, then it is cooled and the separated product is isolated, and the product is identified by thin layer chromatography. This gives 4-amino-1-methyl-3- (5-nitro-2-furyl) -1H-pyrazolo [3,4-d] -pyrimidine with a decomposition point of 305 ° C. The obtained compound is characterized by the following NMR spectra in trifluoroacetic acid δ (ppm) 8.75 (2H, s, exchange), 8.70 (1H, s), 7.60 (1H, d), 7.44 (1H d) 4.26 (3H, s). Claims 1. A process for the preparation of 5-nitrofuran derivatives of the general formula, in which R ± is a lower alkyl group of at least 3 carbon atoms, and the acid addition salts thereof, exemplified by the compound of the formula 2, in which Rj is as defined above, is treated with formamide and the resulting compound of formula (I) is optionally converted into an acid addition salt. 2. A process for the preparation of 5-nitrofuran derivatives of the general formula I, in which Rj is a methyl or ethyl group, and the acid addition salts thereof, characterized in that the compound of formula 2 in which Rj is as defined above and is as follows: formamide, at the reflux temperature, and the resulting compound of formula I is optionally converted to an acid addition salt. 0, HAJ NH2. «¦ *. if A Wit h / zóri 02H <0 n NANH2 i R, Formula Z NxNe i R, Formula l86 535 02N- (°) o, n Hx / HNN m, 21 IL76) 0 ^ x0 H / * W -H (c) Ri N, H 02N N / H (b) R, NH Scheme 1 02N-x0% VN WDL, order 3348 cap. 110 Price PLN 10 PL